JPS6231687B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to an antitumor agent containing α-tocopherol vitamin A acid ester as an active ingredient. Vitamin A acid is already known to have antitumor activity and is said to be effective in preventing or treating experimental tumors that occur in epithelial cells. However, vitamin A acid is extremely toxic, and therefore has not been put to practical use as an antitumor agent until now. The present inventors have conducted various studies to solve these conventional drawbacks, and have found that α-tocopherol vitamin A acid ester (chemical name: tocopheryl retinoate) has antitumor activity and extremely low toxicity. I found it. The α-tocopherol referred to in the present invention is dl-α-
Tocopherol refers to natural mixed tocopherols containing d-α-tocopherol and d-α-tocopherol, and vitamin A acid refers to all-trans or 13-cis type. The 13-cis-type A acid ester is a new substance, and the method for producing it will be explained next. Examples of the method include a method of forming an ester bond between 13-cis-vitamin A acid and α-tocopherol as raw materials, or a method of isomerizing an all-trans vitamin A acid ester to form a 13-cis-type ester. The ester bond may be formed by a known ester forming reaction, such as the method described in Japanese Patent Publication No. 49-26632. As a method for isomerizing, known photoisomerization methods for carotenoids can be applied. Production example 1g of 13-cis-A acid and 1.5g of α-tocopherol
was dissolved in 10 c.c. of dry tetrahydrofuran, and while stirring under a nitrogen stream, 0.9 g of trifluoroacetic anhydride dissolved in 5 c.c. of dry tetrahydrofuran was slowly added dropwise at 0°C. After the dropwise addition, the mixture is allowed to react at room temperature for an additional 2 hours. After the reaction, pour into ice water and extract with 20 c.c. of ether. The ether layer was washed successively with water, dilute alkali, water, and saturated brine, dried over MgSO ₄ and the ether was distilled off to obtain 2.4 g of a yellow oil. this
When applied to a 20 g silica gel column and eluted with hexane:ether=50:1, α-tocopherol-13-cis-vitamin A acid ester is obtained as a yellow oil. Yield: 1.73g Yield: 73% The physical properties of this product are as follows.

【table】

[Table] As described below, the acute toxicity in mice of α-tocopherol vitamin A acid ester, which is the active ingredient of the present invention, is extremely low by all administration routes: oral, intraperitoneal, and intravenous injection.

【represent. 1 Preventive effect on tumor development A 0.2% acetone solution of dimethylbenzanthracene (hereinafter abbreviated as DMBA), a carcinogenic agent, was applied to the hair-removed backs of 10 ICR mice per group for 2 weeks. Starting from the first week after the final administration of DMBA, a solution of 0.06% croton oil in acetone, a solution of 0.06% croton oil in acetone, and the lotion containing the active ingredient of the present invention were sequentially applied to the back once a day for 4 months. Incidentally, the lotion was manufactured by the following method. α-tocopherol vitamin A acid desired amount and polyoxymethylene sorbitan monolaurate
0.5 g was dissolved in 10 g of ethyl alcohol, 6 g of glycerin and purified water were added to make a total of 100 g, and the mixture was thoroughly stirred to obtain a lotion. Next, the test results are shown in the table below.

[Table] As is clear from the test results above, those given croton oil developed tumors due to its secondary stimulation, but those given croton oil and the active ingredient of the present invention at the same time significantly suppressed tumor development. It is being
It is therefore clear that the active ingredients of the invention prevent tumor development. 2. Tumor treatment effect Apply 0.2% DMBA dissolved in olive oil to the backs of hairless mice using a brush three times a week for 2 months. After confirming tumor development, test groups of 5 mice per group are randomly created. α-tocopherol A acid ester is administered topically or orally to these animals,
Changes in the tumor were observed, and the state of the tumor 3 weeks after administration is shown in the following table.

[Table] As is clear from the above test results, the active ingredient of the present invention can be administered by methods such as topical application, oral administration, and injection. When used for the treatment of adults, the dosage is 100 to 1200 mg per day, and in the case of external preparations such as lotions, it is desirable to apply the active ingredient locally several times a day in an amount of 0.01 to 0.5%. Next, specific formulation examples of the present invention will be given, but the present invention is not limited to the following formulation examples. When the active ingredient of the present invention is orally administered, it may be administered in the form of tablets, granules, or powders, and in particular, the granules and powders can be made into unit dosage forms in the form of capsules, if necessary. These solid preparations for oral administration are prepared using commonly used excipients such as silicic anhydride, metasilicic acid, magnesium aluminate, synthetic aluminum silicate, lactose, sugar, corn starch, microcrystalline cellulose, hydroxypropyl starch, or glycine, conjugated agents such as gum arabic, gelatin, tragacanth, hydroxypropylcellulose or polyvinylpyrrolidone,
It may also contain lubricants such as magnesium stearate, talc or silica, disintegrants such as potato starch, calcium carboxymethylcellulose, or wetting agents such as polyethylene glycol, sorbitan monooleate, polyoxyethylene hydrogenated castor oil, sodium lauryl sulfate, and the like. The tablets may be coated according to conventional methods. Oral liquid preparations are aqueous or oily emulsion solutions,
It may be made into a syrup or the like, or it may be a dry product which can be redissolved in a suitable vehicle before use. Such liquid preparations contain commonly used additives such as emulsifying aids such as sorbitol syrup, methyl cellulose, gelatin, hydroxyethyl cellulose, etc., and emulsifying agents such as lecithin, sorbitan monooleate, polyoxyethylene hydrogenated castor oil, and non-aqueous vehicles. For example, fractionated coconut oil, almond oil, peanut oil, preservatives such as methyl p-hydroxybenzoate, propyl p-hydroxybenzoate or sorbic acid may be added. Furthermore, these preparations for oral administration may contain preservatives, stabilizers, etc., if necessary. Next, when using this compound as an injection, it may be in the form of an oil solution, emulsion, or aqueous solution.
These solvents may contain commonly used emulsifiers, stabilizers, etc. Depending on the method of administration, these compositions contain 1% or more of the compound, preferably 5 to 50%.
%. Next, formulation examples are listed to further specifically explain the present invention, but the present invention is not limited to the following formulation examples. Formulation example 1 Oral hard capsule α-tocopherol vitamin A acid ester 25g
and polyoxyethylene castor oil (Nitsukor)
Dissolve 7.5 g of HCO 60) in acetone and then mix with 25 g of silicic anhydride. After evaporating the acetone,
In addition, carboxymethyl cellulose calcium 5
g, 5 g of corn starch, 7.5 g of hydroxypropyl cellulose (HPC-L) and 20 g of microcrystalline cellulose were mixed, and 30 ml of water was added and kneaded.
Granulate. This was granulated using a granulator (manufactured by Fuji Paudal) equipped with a No. 24 mesh (BS) screen.The granules had a moisture content of 5%.
It was dried and sifted through a No. 16 mesh (BS) sieve. Next, these particles are packed in a capsule filling machine.
Capsules are filled with 190mg. Formulation example 2 Oral soft capsule α-tocopherol vitamin A acid ester 50g
and fractionated coconut oil (miglyol 812)
Mix 130g to make a homogeneous solution. gelatin separately
93g, glycerin 19g, D-sorbitol 10g,
A gelatin solution consisting of 0.4 g of ethyl paraoxybenzoate, 0.2 g of propyl paraoxybenzoate, and 0.4 g of titanium oxide was prepared, and this was used as a capsule coating agent, and the content was 180 mg by manual plate punching.
Soft capsules containing the following were produced. Formulation example 3 Injection α-tocopherol vitamin A acid ester 5
g, an appropriate amount of peanut oil, and 1 g of benzyl alcohol are mixed, and the total amount is made up to 100 c.c. using peanut oil. Dispense 1 c.c. of this solution into ampoules using aseptic technique and seal.

Claims (1)

[Claims] 1. An antitumor agent characterized by containing α-tocopherol vitamin A acid ester as an active ingredient.